Macrophage immunobiology

Work team
Macrophage immunobiology
Macrophage immunobiology

Research Projects

Chagas disease is caused by the protozoan parasite Trypanosoma cruzi and is endemic in Central and South America, where it affects about 10 million people. In addition, migration has led to the disease being established in non-endemic countries. Infection involves an acute stage that evolves to a chronic stage where infected individuals may or not may show clinical symptoms or suffer progressive heart disease. Activation of the immune system plays a very important role, however T. cruzi parasite employs different strategies to supress or downregulate the immune system.

Mechanisms involved in the macrophage polarization in T. cruzi infection.

In the mammalian host, the parasites infect the nucleated cells and also the replicating intracellular amastigotes that reside in the cytoplasm of the infected cell as macrophages, dendritic cells and muscle cells. CD4 T cells are important regulators of efficacious anti-parasite immunity. As noted, inflammatory cytokines like TNF and IFN-γ function to activate M1 macrophages to enhance killing of protozoan parasites. Macrophages can also be activated with anti-inflammatory M2 phenotype which play an essential role in homeostasis and tissue repair, however the activation of this profile is detrimental to control infections. We have reported previously that a T. cruzi antigen is able to activate alternatively macrophages in vitro. This profile of activation allows the uncontrolled growth of the parasite within the macrophages. In addition, we have demonstrated that the growth of the parasite in these macrophages depends critically on the level on arginase (Stempin et al. 2002 and 2004). Although the exact role of arginase clearly is not established, this enzyme plays a very important role in a variety of human and experimental diseases. However, how metabolic status regulates macrophage polarization remains not well understood. The mammalian target of rapamycin (mTOR) is a key nutrient/energy sensor that couples nutrient availability to regulation of downstream metabolic processes such as protein synthesis, glycolysis and de novo lipogenesis. It has been recently shown that mTOR pathway regulates macrophage polarization. Therefore we are currently investigating the role of mTOR pathway T. cruzi replication in macrophages.

Molecular and metabolic mechanisms involved in immunosuppression of T lymphocytes during infection caused by T. cruzi.

The relevance of T cells in the control of T. cruzi infection has been demonstrated in human infection and in experimental models. However, the T. cruzi parasite employs different strategies to downregulate the T cell function. These mechanisms can act at the initial time of T cell activation, leading to a state of anergy where lymphocytes do not respond. However, the molecular components that regulate this process during T. cruzi infection are not well understood.

Protein-ubiquitination mediated by E3-ubiquitin ligases is one of the essential mechanisms that regulate tolerance to self-antigens, restricting the activation of the T cell. In addition, T cell anergy involves activation of a genetic program that includes the expression of different E3-ubiquitin ligases that degrade signaling mediators by controlling the abundance or location of these mediators. However, expression of these enzymes in T cells during infections has been implicated in the decreased response of the T cell.

Our findings demonstrate for the first time that this T cell hyporesponsiveness could be linked to an increased expression of an enzyme called GRAIL (Gene related to anergy in Lymphocytes) (Stempin et al. 2016, in revision). In addition, it has been shown that expression of this enzyme can be controlled by mTOR. The participation of these mechanisms during Chagas disease has not been addressed. Therefore in this line of research, we are currently investigating the molecular and metabolic factors involved in immunosuppression of T cells during T. cruzi infection.


  1. Stempin C, Giordanengo L, Gea S, Cerbán F. Alternative activation and increase of Trypanosoma cruzi replication in murine macrophage stimulated by cruzipain, a parasite antigen. J. Leukoc. Biol. 2002; 72:727-734

  2. Giordanengo L, Guiñazú N, Stempin C, Fretes R, Cerbán F, Gea S. Cruzipain, a T. cruzi antigen, conditions the host immune response in favor of parasite. Eur. J. Immunol. 2002; 32:1003-1011.

  3. Stempin CC, Tanos TB, Coso OA, Cerbán FM. Arginase induction promotes Trypanosoma cruzi intracellular replication in Cruzipain-treated J774 cells through the activation of multiple signaling pathways. Eur. J. Immunol. 2004; 34:200-209.

  4. Stempin CC, Garrido V, Dulgerian L, Cerbán F. Cruzipain and SP600125 induce p38 activation, alter NO/arginase balance and favor the survival of Trypanosoma cruzi in macrophages. Acta Tropica 2008; 106:119-127.

  5. Stempin CC, Dulgerian L, Garrido V, Cerbán F. Arginase in parasitic infections: macrophage activation, immunosuppression and intracellular signals. Journal of Biomedicine and Biotechnology. 2010; 2010: 683485.

  6. Dulgerian, LR; Garrido, VV; Stempin, CC and Cerbán, FM. “D-L2 regulates arginase induction and modifies Trypanosoma cruzi survival in macrophages during murine experimental infection. Immunology 2011; 133: 29-40.

  7. Garrido, VV; Dulgerian, LR; Stempin, CC and Cerbán, FM. The increase in mannose receptor recycling favors arginase induction and Trypanosoma cruzi survival in macrophages. International Journal of Biological Sciences 2011; 7: 1257-1272.